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British Journal of Radiology (2003) 76, 459-463
© 2003 British Institute of Radiology
doi: 10.1259/bjr/16316438
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Full Paper

Could assessment of glioma methylene lipid resonance by in vivo 1H-MRS be of clinical value?

P S Murphy, PhD 1 I J Rowland, PhD 1 L Viviers, MBChB 2 M Brada, BSc, FRCP, FRCR 2 M O Leach, PhD, FinstP, FMedSci 1 and A S K Dzik-Jurasz, PhD, FRCS, FRCR 1

1 Cancer Research UK Clinical MR Research Group and 2 Department of Neuro-oncology, The Institute of Cancer Research and The Royal Marsden NHS Trust, Sutton, Surrey SM2 5PT, UK

Correspondence: Dr A S K Dzik-Jurasz, GlaxoSmithKline Pharmaceuticals, 891–995 Greenford Road, Building 5, Floor 3, Room 13, London UB6 0HE


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 Conclusion
 References
 
The potential clinical role of in vivo 1H-MRS (1H-magnetic resonance spectroscopy) lipid methylene resonance measurements of human glioma has been assessed. 20 patients, 14 with low grade and 6 with high grade gliomas have been investigated using single voxel 1H-MRS. Three of the low grade group had undergone transformation by clinical and imaging criteria. Short echo time (TE=20 ms, TR=2500 ms) single voxel Stimulated Echo Acquisition (STEAM) spectra with (acquisitions=64) and without (acquisitions=4) water suppression were acquired. Additionally, T1 weighted (T1W) water spectra (TE=20 ms, TR=888 ms) were acquired pre- and post-injection of Gd-DTPA (0.2 mmol kg-1). The T1W water spectra were used to determine the water proton enhancement occurring within the spectroscopic voxel. The enhancement expressed as a percentage was compared with the lipid methylene peak. All the high grade tumours had significantly higher levels of lipid than low grade tumours (p=0.002). Low grade tumours had significantly less water proton enhancement than transformers (p=0.04) and high grade tumours (p=0.001). The lipid methylene signal correlated strongly with the voxel water enhancement (r2=0.74, p<0.0001). The data support the view that the spectroscopically detected lipid methylene signal may be a useful criterion in grading glioma. The correlation of the lipid methylene signal with blood–brain barrier breakdown suggests that detection of a previously absent 1H-MRS lipid methylene signal in low grade tumours might be an early indicator of transformation.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 Conclusion
 References
 
The clinical management of glioma presents a considerable challenge [1]. The currently available non-invasive diagnostic tools remain limited, requiring surgical biopsy to histologically grade tumours. Furthermore, there are no reliable biomarkers or clinical markers other than tumour grade available for the prognosis of patients on an individual basis. Therefore the development of a methodology enabling non-invasive grading and prognosis of glioma would be of clinical benefit. Morphological imaging criteria offer little to this end, although tumour volume measurements may aid in the study of malignant degeneration or treatment response. Recently, it has been shown that microvascular permeability assessed by dynamic contrast enhanced MRI is associated with progression and treatment response [2]. These studies however await validation and larger studies are required to determine their role in glioma management. Proton magnetic resonance spectroscopy (1H-MRS) on the other hand has received attention for its potential contribution to the non-invasive diagnosis and prognosis of brain tumours [3–5]. This technique can be performed using most clinical MRI scanners at field strengths of 1.5 T or greater. If proven useful therefore, spectroscopic measurements could be incorporated into standard diagnostic MRI protocols to provide additional functional data.

1H-MRS permits localized detection of a number of brain metabolites. Of these metabolites, choline, N-acetylaspartate (NAA), lactate and lipid signals have shown the greatest promise in describing aspects of tumour biology. It is well established that 1H-MRS determined choline levels are frequently elevated in tumours relative to normal tissue [6, 7]. Furthermore, increasing choline levels measured by serial MRS have been shown to coincide with malignant transformation of gliomas [5]. NAA has been shown to arise almost exclusively within neurons [8] and thus reflects neuronal density. During the development of a glioma, these neurons are replaced by glial cells, leading to a reduced or absent NAA signal [9]. As NAA does not derive from cancerous glial cells [8] its absence is only a secondary marker of disease and as such offers limited insight into tumour biology. The 1H-MRS detected lactate resonance in glioma has also received attention [10], though disagreement remains as to the relevance of the signal to the diagnosis and prognosis of glioma [11, 12]. Furthermore, owing to signal overlap with the lipid methylene resonance (1.2 ppm), complex pulse sequences are often required to distinguish the two peaks.

There has previously been interest in the potential clinical usefulness of the 1H-MRS lipid signal acquired from brain tumours [13]. It has been proposed that lipid and other metabolite 1H-MRS signals can be used to grade glioma [14]. This assumption however remains unsubstantiated. The large concentrations of lipid in tumours mean that rapid MRS investigations could contribute to the grading, prognosis and assessment of treatment response.

The current work presents a simple and rapid MRS protocol applied to the study of the lipid methylene resonance in patients with high and low grade glioma. In order to compare the intergroup variability a radiological indicator of tumour grade was required. Although contrast-enhanced imaging is an accepted method of differentiating low and high grade glioma it does not provide a quantitative comparison with a spectroscopically derived parameter due to slice/volume misregistration. For this reason a spectroscopic method to assess contrast enhancement has been implemented using pre and post T1W water spectroscopy to assess gadolinium uptake into the precise volume from which the metabolite signals originate.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 Conclusion
 References
 
Patients
In total, 20 patients were studied (13 male, 7 female). The local institutional ethics committee approved the study and written informed consent was obtained from all patients. Patients had either been treated by surgery (n=7), radiotherapy (n=8) or both (n=2). Three patients were undergoing surveillance only. The mean length of time between the end of the last course of treatment and the MR study was 4.6 years (median 4.5 years and range 1 to 10 years). One patient had been treated by combined surgery and radiotherapy 1 year prior to the current 1H-MRS study. All diagnoses were histologically confirmed on biopsy. 14 patients had a diagnosis of low grade (WHO grade 2) and 6 had a diagnosis of high grade (WHO grade 4) glioma. Three of the low grade tumours had undergone high grade transformation by radiological and clinical criteria. Clinical criteria included the development of new or worsening central nervous system symptoms. Radiologically, the development of enhancement in a lesion where it had not been present previously was taken as indicating transformation to a higher grade. In these three cases the diagnosis of transformation had been made 6 months prior to the current MR study. These three patients were grouped separately for analysis, classified as "low grade with transformation".

MR measurements
Each examination consisted of a standard imaging protocol together with dynamic contrast enhanced imaging and 1H-MRS performed before and after administration of a contrast agent to obtain the metabolic information and spectroscopic water enhancement data. Gadolinium diethylenetriamine-pentaacetic acid (Schering Healthcare Ltd, UK) was used in all studies and was injected as a double bolus dose (0.2 mmol kg-1).

All measurements were performed on a 1.5 T Siemens Vision system (Erlangen, Germany) using the manufacturer's circularly polarized head coil. Using stimulated echo acquisition mode (STEAM) localization, a cubic voxel (volume size between 11.0 ml and 15.6 ml (mean=11.7 ml)) was placed in the centre of the abnormality detected on axial fluid attenuated inversion recovery (FLAIR) imaging. The voxel position was chosen with T2 weighted coronal fast spin echo (FSE) and axial FLAIR images. Prior to spectroscopy global shimming was undertaken using either multi-angle projection SHIM (MAP-SHIM) or the three-dimensional non-iterative shimming sequence provided by Heid [15]. Global shimming was followed by manual shimming (using the STEAM sequence with the water suppression pulse voltages set to zero). Short echo time (TE=20 ms) spectra were acquired pre-contrast with water suppression. At short TE the repetition time (TR) was set to 2500 ms with 64 averages (2 min 40 s acquisition time). In addition, a spectrum at TE=135 ms and TR=2500 ms was used to qualitatively determine the presence of lactate. With the water suppression pulses set to zero volts, spectra were acquired pre-contrast with TR=2500 ms, TE=20ms (proton density weighted, PDW) and TR=888 ms, TE=20 ms (T1 weighted, T1W). Post-contrast only the T1W water spectrum with TR=888 ms, TE=20 ms was acquired. For all water spectra, the receiver gain was reduced and spectra acquired with four averages. Post-contrast water spectra were acquired 12±1 min after injection of the contrast agent.

Post-processing
Spectra were fitted in the time domain using MRUI version 96.3 (Magnetic Resonance User Interface) software with the VARPRO (Variable Projection) algorithm [16]. Residual water was first removed using the Hankel Lanczos Singular Value Decomposition (HLSVD) technique [17], followed by fitting the metabolite peaks with Lorentzian lineshapes. To allow a quantitative comparison of metabolite signals between different patients the metabolite lipid signals were divided by the PDW water signal after appropriate correction for the receiver gain. In order to determine the percentage water signal enhancement within the voxel, the pre- and post-contrast T1W spectra were used. To quantify this value which we have termed the intravoxel enhancement (IVE), the following equation was used: Go


Statistics
Comparison between groups in the lipid signal intensity and water enhancement was done using the Mann–Whitney U-test. A Spearman correlation test was performed in order to determine associations between variables. Values of p<0.05 were considered to be statistically significant.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 Conclusion
 References
 
Example metabolite spectra are presented in Figure 1Go from a low grade and high grade tumour, respectively. The lipid methyl (0.9 ppm) and methylene (1.3 ppm) resonances dominate the spectrum in Figure 1bGo. Only a small amount of signal is visible in this region of the spectrum from the low grade tumour (Figure 1aGo). The spectra demonstrate the large variability in lipid concentrations between short echo time spectra obtained from tumours of different grades. Lactate was observed in two of the 135 ms echo time spectra (both from high grade tumours). The level, however, was judged not to contribute significantly to the 20 ms echo time lipid methylene resonance owing to the considerable intensity of the lipid signals in these two cases.



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  		Figure 1. (a) A short echo time spectrum from a low grade tumour showing no contrast enhancement as evidenced by imaging and water 1H-MRS. The major resonances are indicated: Cho, choline; Cre, creatine; and NAA, N-acetylaspartate. (b). A short echo time spectrum from a histologically verified contrast enhancing high grade glioma. The most prominent peaks observed are the lipid methylene and methyl signals, labelled as lip(-CH2-) and lip(-CH3), respectively.

 
In the quantitative treatment of results, the lipid methylene resonance was normalized by dividing by the PDW water signal and plotted against the two tumour grades as presented in Figure 2aGo. The low grade group demonstrated statistically lower values than the high grade group (p=0.002) but no significant difference was detected between transformers and the high grade (p=0.14) or low grade (p=0.06) group. Figure 2aGo shows the low grade group with transformation to be positioned between the high and low grade groups. One aim of this study was to investigate the utility of using spectroscopic voxel water enhancement as an index by which the spectroscopic parameters could be compared. The values for the IVE are shown in Figure 2bGo plotted against tumour grade. The enhancement in low grade tumours is significantly lower than in high grade tumours (p=0.001) or transformers (p=0.04). No difference was detected between transformers and high grade tumours (p=0.09).



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  		Figure 2. (a) The relationship between glioma grade and the normalized lipid methylene signal. (b) The intravoxel enhancement (IVE) values determined spectroscopically and categorized by tumour grade.

 
Figure 3Go demonstrates a plot of the IVE versus the normalized lipid methylene signal. A strong linear correlation is observed (r2=0.74 and p=0.0001). The data are categorized as (a) histologically verified low grade tumours, (b) histologically verified low grade tumours with radiological and clinical transformation and (c) histologically verified high grade tumours.



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  		Figure 3. A correlation between the normalized lipid methylene signal with the percentage intravoxel enhancement (IVE). For the linear regression, r2=0.74 and p=0.0002.

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
Conclusion
 References
 
The current study suggests that the methylene lipid resonance detected by in vivo 1H-MRS could be useful in grading glioma and in the early detection of high grade transformation. Our results support those of others [18, 19] demonstrating a correlation between the 1H-MRS visible lipid resonance and tumour grade. Several spectroscopic and biological features of glioma potentially explain the correlation. Necrosis remains the key diagnostic criterion for grade IV tumour [20] as well as being a strong prognostic indicator [21]. Since the 1H-MRS visible lipid resonance is strongly associated with the presence and amount of necrosis in glioma [22, 23] then given the appropriate hardware sensitivity an association between tumour grade and spectroscopically detected lipid would be anticipated. The principal lipid resonance is that due to the methylene group at 1.3 ppm attributed to the fatty acyl protons. Evidence points to these lipids residing as intracellular or extracellular triglyceride droplets [24–26] rather than intact or partially degraded membrane as previously reported.

The specificity of 1H-MRS for grading however remains limited since grade III tumours do not invariably return a lipid signal [19]. The presence or absence of a lipid signal will also be significantly influenced by sequence parameters, most notably the echo time. The inherently short T2 of lipids results in significant signal loss with increasing echo time. The 20 ms echo time employed in the current study is considerably shorter than the majority of previous studies. The absence of grade III tumours and the limited number of samples is therefore likely to have influenced the current findings. However, the study was focused on lipids and the shorter echo time was employed to optimize that signal. Lactate was detected in only two high grade tumours and therefore did not influence the spectra from low grade and transformed tumours. In addition, when present the lactate signal was considerably less intense than that of the lipid.

The apparent stratification of low grade tumours with transformation between low grade and high grade cases (Figure 3Go) raises the possibility that the development of, or increase in the methylene lipid signal intensity, may be an early marker or predictor of transformation. Since all three individuals in this study had transformed at the time of examination the predictive potential remains to be tested. An increased sample number would also have helped to define the apparent trend between groups in Figure 2aGo. It may however be that 1H-MRS could detect the necrosis associated with high grade status prior to symptomatic change in the patient. This correlation is of course dependent on the biological assumptions made about intravoxel enhancement. Following administration of intravenous contrast, tumoural enhancement has long been accepted to represent a breakdown in the integrity of the blood–brain barrier. It is acknowledged though that some high grade tumours may not enhance and therefore enhancement is not a gold standard for confirming high grade status. We believe however that the acquisition of data from a voxel encompassing much of the tumour volume will have considerable sensitivity to the presence of enhancement. In addition, methodologically it provides a simple quantitative measure of enhancement. It is suggested therefore that future studies examining the use of 1H-MRS in the management of low grade glioma should incorporate a search for alterations in the lipid profile, particularly in relation to the time of transformation. This would complement the finding that the 1H-MRS choline resonance [5] and blood volume [27] in these tumours appear to have a predictive role.


   Conclusion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusion
References
 
It has been shown that lipid methylene levels correlate with high grade and low grade tumour status, thus suggesting a role for the technique in grading. In addition, the use of spectroscopic water enhancement measurement allows direct comparisons to be made between contrast agent uptake and metabolic characteristics. The potential use of lipid measurements for judging the stage and hence prognosis in low grade tumours is suggested by the apparent gradual increase in both enhancement and lipid levels following low grade tumour transformation. The enhancement alone, however, is not necessarily useful for prognosis as some high grade tumours do not enhance and blood–brain barrier degradation is required prior to measuring significant contrast agent uptake. The increase in lipid levels believed to be associated with necrosis could be used prior to this in low grade tumours. High lipid levels in low grade tumours could be an early marker of transformation prior to the patient becoming symptomatic. Serial investigations are currently being undertaken to further define the prognostic relevance of 1H-MRS lipid measurements in clinical studies of glioma.


   Acknowledgments
 
The MRUI software package was kindly provided by the participants of the EU network programmes: Human capital and Mobility, CHRX-CT94-0432 and Training and Mobility of Researchers, ERB-FMRX-CT970160.


   Footnotes
 
Current address for I J Rowland: Danish Research Centre for Magnetic Resonance, Copenhagen University Hospital, Hvidovre, Kettegårds Allé 30, DK-2650 Hvidovre, Denmark. Back

Funding from Cancer Research UK grant SP1780/0103 the Medical Research Council (G9326054MA; G78/4595) are gratefully acknowledged. Back

Received for publication August 27, 2002. Revision received March 12, 2003. Accepted for publication April 26, 2003.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusion
 References
 

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